JAM-A: Junctional Adhesion Molecule-A or Janus Acting Mediator in Atherosclerosis

201 Pages·2014·6.14 MB·English

JAM-A:
Junctional Adhesion
Molecule-A

or

Janus Acting Mediator in
Atherosclerosis

Von der Fakultät für Mathematik, Informatik und Naturwissenschaften der RWTH
Aachen University zur Erlangung des akademischen Grades eines Doktors der
Naturwissenschaften genehmigte Dissertation
vorgelegt von
Diplom-Biologe
Martin Schmitt
aus Düren, Nordrhein-Westfalen, Deutschland
Berichter:
Univ.-Prof. Dr. med. Christian Weber
Univ.-Prof. Dr. rer. nat. Marc Spehr
Prof. Tilman Hackeng, PhD
Univ. Prof. Dr. rer nat. Jürgen Bernhagen
Tag der mündlichen Prüfung: 18. Juni 2014
Diese Dissertation ist auf den Internetseiten der Hochschulbibliothek online
verfügbar.
Printed by: Proefschriftmaken.nl || Uitgeverij BOXPress
Published by: Uitgeverij BOXPress, s’Hertogenbosch
ISBN: 978-90-8891-903-9
© 2014 Martin Schmitt, Munich
This PhD-thesis was completed within the

Euregio Cardiovascular (EuCAR)
International Research Training Group (IRTG) 1508
‘Arterial remodeling’

at

RWTH Aachen University

Spokesperson:
Univ.-Prof. dr. rer. nat. Jürgen Bernhagen
Institute of Biochemistry and Molecular Cell Biology

and

Maastricht University

Spokesperson:
Prof. dr. Tilman Hackeng, PhD
School for Cardiovascular Diseases (CARIM)

Contents

Chapter 1 General Introduction 7

Methods and Results

Chapter 2 Endothelial JAM-A guides monocytes into flow-dependent 38
predilection sites of atherosclerosis

Chapter 3 Atherogenic mononuclear cell recruitment is facilitated by 74
oxidized lipoprotein-induced endothelial junctional
adhesion molecule-A redistribution

Chapter 4 TNF- and IFN- promote lymphocyte adhesion to 98
endothelial junctional regions facilitating transendothelial
migration

Chapter 5 Hyperreactivity of junctional adhesion molecule A-deficient 126
platelets accelerates atherosclerosis in mice

Chapter 6 General Discussion 153

Summary 168
Zusammenfassung 173
Samenvatting 177
Curriculum Vitae 182
List of Abbreviations 188
Acknowledgement 194
1
Contribution to the General Introduction (chapter 1):
1
This part was solely written by Martin Schmitt.
1

Chapter 1
1

General
Introduction
CHAPTER 1
1 Atherosclerosis
Atherosclerosis is a chronic inflammation of the arterial wall and causes inter
alia rearrangement of cellular and subcellular components. Besides some other
diseases like thromboembolic disease, rhythm disorders and hypertension,
atherosclerosis is the main contributor to cardiovascular diseases.
Atherosclerotic lesions are mediated by modified low density lipoproteins (LDL)
triggered immune cell influx, accumulation of dead mononuclear and vascular
cells, reorganization of smooth muscle cells (SMC) as well as deposition of
extracellular matrix like collagen. Most atherosclerotic lesions cause luminal
narrowing comprising altered shear stress conditions, until unstable lesion
rupture releases prothrombotic material into the lumen, initiating coagulation
and causing occlusion. Dependent on the site of occlusion this may lead to
myocardial infarction or stroke, two of the most important sources for illness and
death in developed countries1-3.
The onset of atherosclerosis is represented by the formation of a “fatty
streak”, an accumulation of highly lipid-laden macrophages4. In a classification
of plaque stages by Virmani and colleagues those intimal xanthomas still count
for the non-atherosclerotic intimal lesions without necrotic core or fibrous
depositions covering the lipid core, often referred to as fibrous cap5. Intimal
macrophages phagocytose excess lipids, transform into “foam cells” and
contribute together with activated endothelial cells and further intimal immune
cells to the inflammatory milieu by secreting a great variety of cytokines, like
Interleukin (IL)-1 and -6, and tumor necrosis factor (TNF)-α6, chemokines and
proteases. Progressive atherosclerotic lesions finally evolve from this enhanced
secretion of atherogenic factors. Those lesion stages were categorized by
Virmani et al. as pathological intimal thickening comprising SMCs in a
proteoglycan-rich matrix and extracellular lipid accumulations and as fibrous
cap atheroma containing a well-formed necrotic core and a covering fibrous
cap. Finally, matrix-metallo protease mediated weakening of the fibrous cap
results in a higher susceptibility to plaque rupture followed by vessel occlusion.
The role of disturbed flow in atherogenesis
Besides the generally accepted notion that hyperlipidemia induced excess of
modified LDL in the vessel wall is responsible for activation of the endothelial
cell layer and thus increasing mononuclear cell recruitment1, 3, also alterations in
laminar shear stress, preferentially occurring at branching points or curvatures
activate the endothelium and cause enhanced mononuclear cell extravasation
into the vessel wall7, 8. First evidence for shear stress dependent mononuclear
cell extravasation was found in the mid-eighties by differently localizing
10